Exploiting Recurrent Chromatin Modifier Mutations for Prostate Cancer Targeted Therapy
Abstract
Background: Prostate cancer (PC) is the second leading cause of cancer death in men. This high mortality burden is primarily due to metastatic disease: PC that has spread beyond to prostate to colonize and grow in distant organs. Metastatic PC is currently being treated by blocking the availability of androgens like testosterone that fuel tumor growth and cellular survival. Unfortunately, this strategy is only effective at suppressing PC for a limited amount of time before it recurs as a therapy-resistant form. Recent large-scale studies that characterized the genetic changes that occur in metastatic PC have uncovered a large subset of these tumors (~20%) that harbor deletions or mutations in genes that regulate the epigenome. The epigenome consists of chemical modifications made to DNA and the proteins that organize DNA, termed chromatin. These chemical changes regulate the expression of genes by changing the three-dimensional structure of chromosomes and regulate which (and how) genes are turned off or turned on, also termed “expressed.” Currently, the role these chromatin-modifying enzymes play in PC is unknown. Even less is known about how mutations of these factors mediate resistance to therapy. Hypotheses/Objectives: This research project is designed to test the hypothesis that mutations in different chromatin-modifying (CM) enzymes result in similar effects on the cell because they feed into the same biological processes and pathways that promote cell survival, cell growth, and resistance to treatment. A corollary of this hypothesis is that different tumors, with mutations in different chromatin-modifying enzymes, can be targeted by the same therapy designed to reverse or suppress the downstream effects of these mutations. In Aim 1 of our proposal, we will identify the chromatin-modifying genes whose loss leads to therapy resistance and determine how those factors are related to each other. In Aim 2, we will investigate the biological basis of this resistance by measuring global changes to gene regulation. Lastly, in Aim 3 we will devise a therapeutic strategy to be used alongside androgen blockade specifically in PCs that harbor alterations in genes that modify or interact with chromatin. Impact: The field of prostate cancer research will be advanced by this study in the following ways: 1. We will define a subset of chromatin-interacting proteins that predict whether a cancer is resistant or responsive to specific treatments—particularly drugs that target the androgen receptor (AR). 2. We will deepen our understanding of how mutations in chromatin modifiers affect the regulation of genes in prostate cancer. 3. Despite having different roles within the cell, we will define a set of genes that, when mutated, result in similar biological effects. 4. By furthering our understanding of how similar biological effects can be achieved through different means, this study will guide clinical trial design and drug development. Prostate cancer patients with tumors that harbor mutations to chromatin modifiers (~20% of patients with metastatic PC) are currently treated with the same therapy as those that do not. However, mutations to certain chromatin-modifying enzymes can render cancers less sensitive to conventional therapy. There may be vulnerabilities that emerge because of these mutations or ways to counteract the effects of these mutations using combination drug therapies. We anticipate that this study will enhance clinical efforts to use information gained through genomic sequencing to best treat patients by identifying therapeutics that can selectively target cancer cells with specific mutations. Since several candidate therapies are already in clinical trials for PC, we anticipate our study will have an immediate impact on clinical research by shedding light on why some patients respond to these therapies and others do not. Our studies may also identify new strategies to improve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910383
Entities
People
- Michael Nyquist
Organizations
- Fred Hutchinson Cancer Center
- United States Army